The present invention relates to a process for the production of a naphthyridine carboxylic acid derivative having antibacterial activity.
EP 688772 discloses novel naphthyridine carboxylic acid derivatives, including anhydrous (R,S)-7-(3-aminomethyl-4-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid of formula I, having antibacterial activity. 
WO 98/42705 (published after the priority date of the present application) discloses (R,S)-7-(3-aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate and hydrates thereof including the sesquihydrate (the xe2x80x9cmethanesulfonate sesquihydratexe2x80x9d). WO 98/42705 discloses a process for the production of the methanesulfonate sesquihydrate comprising reaction of the corresponding free base with methanesulfonic acid in dichloromethane/ethanol followed by recrystallisation of the resulting crude salt anhydrate from either water:acetone (10:7 v/v), or water:ethanol (1:2 v/v). The overall yield for this two step process is 70-80%. An alternative process for the production of the methanesulfonate sesquihydrate described in WO 98/42705 comprises exposing a solvate of the methanesulfonate (ethanol 0.11%) to high relative humidity (nitrogen greater than 93% humidity).
The present invention relates to an improved process for the production of the methanesulfonate sesquihydrate which comprises direct salt and hydrate formation.
According to the invention there is provided a process for the production of 7-(3-aminomethyl-4-syn-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate sesquihydrate which comprises reacting 7-(3-aminomethyl-4-syn-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and methanesulfonic acid in a solvent comprising at least one water miscible cosolvent and water, and isolating the resulting solid product.
The 7-(3-aminomethyl-4-syn-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (hereinafter referred to as xe2x80x9cthe free basexe2x80x9d) used in the process of the invention may be prepared as described in EP 688772.
Water miscible cosolvents which may be used in the process of the invention include C1-8 alcohols, acetonitrile and dimethylformamide. The water miscible cosolvent is preferably a C1-4 alcohol or a mixture thereof, e.g. methanol, ethanol and propanol; the preferred C1-4 alcohol is isopropanol.
In addition to at least one water miscible cosolvent and water the solvent may contain other components, such as C1-4 haloalkanes. However, the solvent preferably comprises essentially of a water miscible cosolvent and water.
Suitable ratios of water miscible cosolvent:water for use in the process of the invention include ratios in the range 10:1 to 1:2 v/v, preferred ratios are in the range 10:1 to 1:1 v/v, more preferably a ratio of water miscible cosolvent; water of 2:1 v/v is used.
Any suitable ratio of free base to solvent may be used, for example, a ratio of up to 1:100 w/v, particularly a ratio of about 1:9 w/v.
The process of the invention may suitably use from 0.7 to  greater than 3 mole equivalents of methanesulfonic acid, preferably 0.7 to 1.5 equivalents, more preferably 0.9 to 1.5 equivalents, especially about 1.0 equivalent of methanesulfonic acid (based on the free base).
The mixture of the free base and methanesulfonic acid may be warmed in the solvent to aid dissolution. On cooling the methanesulfonate sesquihydrate will crystallise out of solution. To aid crystallisation the solution may be seeded with a small quantity of solid methanesulfonate sesquihydrate. In order to obtain polymorphically pure methanesulfonate sesquihydrate it is preferable that seeding of the solution is completed before crystallisation begins. Seeding of the crystallisation solution is preferably performed at a temperature xe2x89xa725xc2x0 C., for example at a temperature of about 30xc2x0 C.
The process of the invention may be used to produce racemic methanesulfonate sesquihydrate or may be used for the production of enantiomerically enriched or enantiomerically pure methanesulfonate sesquihydrate, using racemic or enantiomerically enriched or enantiomerically pure free base. Enantiomerically enriched or enantiomerically pure free base may be prepared by resolution of the racemic free base, e.g. by chiral HPLC.
The process according to the invention has the advantage that direct salt formation eliminates one step in the synthesis and gives a high yield of high purity methanesulfonate sesquihydrate. In turn these advantages result in improved throughput and savings in labour and materials costs during manufacture.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
The invention is illustrated by the following example. However, it should be understood that the example is intended to illustrate but not in any manner limit the scope of the invention.